The causative mechanism of many diseases is the over-activity of a biological pathway. A peptide that can reduce the activity of the biological pathway can be effective in the prophylaxis and/or treatment of the disease caused by the over activity of the biological pathway. Similarly the causative mechanism of many diseases is the over production of a biological molecule. A peptide that can reduce the production of the biological molecule or block the activity of the over produced biological molecule can be effective in the prophylaxis and/or treatment of the disease caused by the over production of the biological molecule.
Conversely, the causative mechanism of many diseases is the under activity of a biological pathway. A peptide that can increase the activity of the biological pathway can be effective in the prophylaxis and/or treatment of the disease caused by the under activity of the biological pathway. Similarly, the causative mechanism of many diseases is the under production of a biological molecule. A peptide that can increase the production of the biological molecule or mimic the biological activity of the under produced biological molecule can be effective in the prophylaxis and/or treatment of the disease caused by the under production of the biological molecule.
Caveolins are cholesterol binding proteins that can potentially regulate a variety of signal transduction pathways (Smart et al., (1999) Mol. Cell. Biol. 19, 7289-7304; Kurzchalia & Parton, (1999) Curr. Opin. Cell. Biol. 11, 424-431). For example, numerous researchers have demonstrated localization of proteins in caveolae, interaction of these proteins with caveolins, and the ability of overexpressed caveolins or peptides derived from caveolins to suppress or stimulate signaling functions in vitro or in cultured cells (Li et al., (1996) J. Biol. Chem. 271, 29182-29190; Razani et al., (1999) J. Biol. Chem. 274, 26353-26360; Nasu et al., (1998) Nat. Med. 4, 1062-1064; Garcia-Cardena et al., (1997) J. Biol. Chem. 272, 25437-25440). However, the importance of caveolins as modulators of signal transduction in vivo is controversial since caveolins-1 and -3, per se, are cholesterol binding proteins that deliver cholesterol from the endoplasmic reticulum to the plasmalemma thereby regulating signal transduction indirectly by modulating the cholesterol content of lipid raft domains and caveolae (Roy et al., (1999) Nat. Cell Biol. 1, 98-105; Sternberg et al., (1999) Nat. Cell Biol. 1, E35-37).
Studies have focused on the subcellular trafficking and regulation of endothelial nitric oxide synthase (eNOS). eNOS derived NO is necessary for the maintenance of systemic blood pressure, vascular remodeling, angiogenesis and wound healing (Huang et al., (1995) Nature 377, 239-242; Murohara et al., (1998) J. Clin. Invest. 101, 2567-0.2578; Rudic et al., (1998) J. Clin. Invest. 101, 731-736; Lee et al., (1999) Am. J. Physiol. 277, H1600-1608). eNOS is a dually acylated, peripheral membrane protein that targets to lipid raft domains and caveolae (Garcia-Cardena et al., (1996) Proc. Natl. Acad. Sci. USA 93, 6448-6453; Liu et al., (1997) J. Cell Biol. 137, 1525-1535). In caveolae, eNOS can physically interact with caveolins-1 and -3 by binding to their putative scaffolding domain located between amino acids 82-101 (Li et al., (1996) J. Biol. Chem. 271, 29182-29190) and this interaction, renders eNOS in its “less active” state (Garcia-Cardena et al., (1997) J. Biol. Chem. 272, 25437-25440; Ju et al., (1997) J. Biol. Chem. 272, 18522-18525; Michel et al., (1997) J. Biol. Chem. 272, 25907-25912). The data for this model was largely elucidated in vitro using overexpression systems, fusion proteins or yeast-two hybrid screening to map the interacting domains.
In support of caveolin as a negative regulator of eNOS are studies showing that peptides derived from the scaffolding domain of caveolin-1 will disrupt the binding of eNOS to caveolin and dose-dependently inhibit NOS activity in vitro (IC50=1-3 μM) by slowing electron flux from the reductase to the oxygenase domain of NOS (Garcia-Cardena et al., (1997) J. Biol. Chem. 272, 25437-25440; Ju et al., (1997) J. Biol. Chem. 272, 18522-18525; Ghosh et al., (1998) J. Biol. Chem. 273, 22267-22271).
Treatment of one or more cells with a peptide comprising at least one caveolin scaffolding domain has resulted in the reduction and/or elimination of one or more conditions or afflictions of the treated tissue, organ or organism. For example, treatment with a peptide comprising at least one caveolin scaffolding domain has been shown to reduce or eliminate inflammation and tumor cell angiogenesis and proliferation. (See U.S. Pat. No. 8,349,798, which is incorporated herein by reference.)
Multiple sclerosis (MS) and neuromyelitis optica (NMO) are diseases of the central nervous system (CNS) that damage the myelin sheath surrounding the nerve cells, leading to visual disturbances, muscle weakness, loss of coordination, numbness, and reduced mental function, among other symptoms. While the causes of these diseases are uncertain, some believe them to be autoimmune disorders. Uveitis is inflammation of the uvea, the middle layer of the eye, which is known to occur in some autoimmune diseases such as rheumatoid arthritis and ankylosing spondylitis. Symptoms may include eye pain, blurring of vision, light sensitivity and decreased vision. There are no known cures for these debilitating diseases and other autoimmune disorders—treatment is primarily palliative, and in many cases, minimally effective in allowing disease sufferers to maintain a reasonable quality of life.
Accordingly, the need exists for new approaches for the prophylaxis and/or treatment of autoimmune diseases and inflammatory diseases. The present invention is directed to such a need.